REGULATION OF TRANSCRIPTION OF IMMUNOGLOBULIN GERM-LINE GAMMA-1 RNA - ANALYSIS OF THE PROMOTER ENHANCER

Antibody class switching is achieved by recombinations between switch (S) regions which consist of tandemly repeated sequences located 5' to Ig heavy chain constant (C(H)) region genes. RNA transcripts from specific unrearranged or germ-line Ig C(H) genes are induced in IgM+ B cells prior to their undergoing class switch recombination to the same C(H) genes. Thus, the antibody class switch appears to be directed by induction of accessibility, as assayed by transcription of germ line C(H) genes. For example, IL-4 induces transcripts from the mouse germ-line C-gamma-1 and C-epsilon genes to which it also directs switch recombination. We report here that the 150 bp region upstream of the first initiation site of RNA transcribed from the murine germ-line C-gamma-1 gene, contains promoter and enhancer elements responsible for basal level transcription and inducibility by anti-Ig phorbol myristate acetate (PMA) and for synergy of these inducers with IL-4 in a surface IgM+ B cell line, L10A6.2 and a surface IgG2a+ B cell line, A20.3. Linker-scanning mutations demonstrated that multiple interdependent elements are required for inducibility by PMA and also for synergy with IL-4. Within the 150 bp region are several consensus sequences that bind known or putative transcription factors, including a C/EBP binding site-IL-4 responsive element, four CACCC boxes, a PU box, a TGF-beta inhibitory element (TIE), an alpha-beta-interferon response element (alpha-beta-IRE) and an AP-3 site. The relationship between transcription regulated by these elements and the regulation of endogenous germ-line gamma-1 transcripts and switching to IgG1 is discussed.